1. Field of the Invention
The present invention relates to a process for preparing Cefepime and cephalosporin analogues, i.e. Cefpirome and Cefquinome.
2. Discussion of the Background Art
U.S. patent application Ser. No. 10/916,532, filed on Aug. 12, 2004 (which is a continuation of U.S. patent application Ser. No. 10/821,986 filed on Apr. 12, 2004) describes a process for preparing cephalosporins of formula
characterised by a 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic chain in the 7-position of 7-ACA and its derivatives of formula
in which R2 can have different meanings including CH2OCOCH3 for 7-ACA, being the cefotaxime nucleus, or
for 7-ACT, being the ceftriaxone nucleus and
for Furaca, being the ceftiofur nucleus.
In said application, the synthesis takes place in two passages: the first consists of preparing an intermediate of formula
by reacting a compound of formula (I)
suitably silylated, with a compound of formula (V)
in which X is Cl or Br, Y is Cl, or O—CH═N+(CH3)2Cl−, isolating a compound of aforegiven formula (IV) in which X is Cl or Br and the carboxyl is salified with benzathine.
This procedure has however proved inapplicable in the case of compounds of formula (IV) containing a strongly basic substituent R2 of the following type:

In this respect the aforesaid basic group R2 forms an internal salt with the carboxyl group in the 4-position, which is hence present as COO− and does not enable the benzathine to salify the carboxyl.
This assertion is confirmed, for example, by US Patent Application 2003/0199712 in which a process is claimed (claim 5) for preparing a compound of formula (II) by passing via a compound similar to that of formula (IV), but in which the carboxyl can be a carboxylate ion, while the substituent in the 3-position can have one of the three aforesaid meanings for R2, thus giving rise to an internal salt between the carboxylate ion and the basic group indicated as R2.
It is therefore evident that the presence of the strongly basic group in the 3-position, in the case of the compound of formula (IV), gives rise to an internal salt, at least according to the expectations of one skilled in the art, while the benzathine salt alternative has proved to be impractical.